Significance Of the xenotransplant models developed for the study of human physiology, the mouse with severe combined immunodeficiency (SCID), or SCID-hu, has been the most widely used for this purpose. The SCID-hu mouse has clearly provided an important model by allowing the investigation of response of human tissues in an in vivo setting. While many essential questions have been addressed with this model, it is well-recognized that the SCID-hu mouse does not parallel all aspects of human physiology or truly allow for the test of response of a primate system to therapeutic strategies. As gene therapy, for example, continues to be explored for potential human clinical application, the need for relevant and predictive primate models for preclinical testing becomes greater. Objectives One of the most efficient methods for inducing tolerance to foreign cells is by introducing the cells to the fetus in utero when it is in a [unreadable]preimmune[unreadable] state. In order to develop a human:rhesus xenogeneic model, human HSC were transplanted into fetal rhesus recipients in the late first trimester. Results Initial studies have focused on transplant of HSC derived from human cord blood collections. Four of five rhesus fetuses transplanted were delivered uneventfully at term, and three of the four were found to be positive for male cells by PCR in blood and marrow pre and/or postnatally. Four weeks post-transplant, one fetus was delivered by hysterotomy and a complete tissue harvest performed in order to fully evaluate engraftment. Male cells were identified in fetal liver, bone marrow, blood, and spleen, although the percent of donor cells was low. Future Directions Because the percent of donor cells in engrafted animals is low, methods for enhancing engraftment will be explored by performing multiple transplants, using human hematopoietic cytokines to selectively expand the human donor cell population, and boosting infants postnatally. KEYWORDS fetus, tolerance, stem cell, In Utero transplantation, rhesus human chimera